3β-[(6-デオキシ-α-L-マンノピラノシル)オキシ]-5,14-ジヒドロキシ-19-オキソ-5β,14β-カルダ-20(22)-エノリド

IDENTIFICATION AND USE: Convallotoxin is a cardiac glycoside. A phytotoxin from the flowers of Adonis vernalis, Convallaria majalis (Lily of the Valley), Ornthogalum umbellatum and Antiaris toxicaria. The aglycone is convallatoxigenin and the sugar is a rhamnose. Convallatoxin is used in acute and chronic congestive heart-failure and paroxysmal tachycardia. HUMAN STUDIES: Convallotoxin induced cytostatic and cytotoxic effects in human lung A549 cells. Convallotoxin inhibited the Na,K-ATPase in A549 cells at nM concentrations. ANIMAL STUDIES: When administered in a single iv injection at minute to lethal doses to rats or cats, convallatoxin caused vascular disorders in the heart, liver, and kidneys. When injected daily at doses corresponding to 0.2 to 0.4 LD100 for 15 days, it caused dystrophic changes and increased the infiltration and proliferation processes. When injected iv into mice, the LD50 value of convallatoxin was 6.3 mg/kg. The glycoside caused tremor, convulsions, and paralysis of the limbs and affected respiration. The preparation caused disorders in the cardiac activity and a transient coronary insufficiency. The effects of a single or repeated ip injections of convallatoxin on the histology of the heart, liver, kidney, spleen, and lungs was studied in mice, rats, and cats. A single injection dilated blood vessels in the heart, liver, and kidneys, caused hemorrhage in the liver, and caused an infiltrative-proliferative effect in the heart and liver. After chronic injections, the infiltrative-proliferative effect was more pronounced than after the acute administration, and dystrophic changes were observed in the liver. ECOTOXICITY STUDIES: Convallatoxin (20 uM) could significantly prolong the lifespan of wild-type Caenorhabditis elegans up to 16.3% through daf-16, but not sir-2.1 signalling and increased thermotolerance and resistance to paraquat-induced oxidative stress. Convallatoxin also improved pharyngeal pumping, locomotion, reduced lipofuscin accumulation and reactive oxygen species levels in C. elegans, which were attributed to hormesis, free radical-scavenging effects in vivo, and up-regulation of stress resistance-related proteins, such as SOD-3 and HSP-16.1. Furthermore, aging-associated genes daf-16, sod-3, and ctl-2 also appeared to contribute to the stress-resistance effect of convallatoxin.

Convallatoxin (CNT) is classified as a cardiac glycoside. Cardiac glycosides are well known Na+/K+-ATPase inhibitors, and some of them are used to treat congestive heart failure and atrial arrhythmias. Recent studies have reported that cardiac glycosides have potential as anticancer agents. CNT exerts cytotoxic effects on a number of cancer and normal cell lines and induces apoptosis by increasing caspase-3 and poly ADP ribose polymerase (PARP) cleavage. Moreover, dose- and time-dependent autophagic activity was detected in CNT-treated cells, and mammalian target of rapamycin (mTOR)/p70S6K signal pathway inhibition was observed. Notably, CNT inhibits human umbilical vein endothelial cell (HUVEC) growth and exerts anti-angiogenic activity in vitro and in vivo. (A15340)

/ALTERNATIVE and IN VITRO TESTS/ Convallatoxin showed potent cytotoxic activity when assayed against Eagle's KB strain of human epidermoid carcinoma and in a disk-plate assay against kb cells. The results suggested that cytotoxicity is associated with an unsaturated lactone either attached to position 17 by a carbon-carbon bond or fused to ring d across the 16,17-position. Thus, the cardiac principles have either a cardenolide ring or a bufadienolide ring attached to position 17. The data also shows that the glycosides were more active than the corresponding aglycones and that the cardenolide and bufadienolide rings were equally effective in confering activity.

/ALTERNATIVE and IN VITRO TESTS/ Cardiac glycosides consist of a large family of naturally derived compounds that are clinically used to treat congestive heart failure, and also present anticancer properties. In this study, the cytotoxic effects of two cardenolides, digitoxigenin monodigitoxoside (DGX) and convallatoxin (CON) were screened in four human tumor cell lines. Both compounds showed anti-proliferative effects in all tumor cells, at nanomolar concentrations. Since the human lung cancer cell line A549 was the most sensitive, we investigated the anti-proliferative, anti-migratory and anti-invasive effects of these cardenolides. DGX and CON reduced A549 cell migration, being able to reduce more than 90% of cell invasion. Their effects on the expression of key regulators of metastatic mechanism showed decreased levels of MMP-2, MMP-9 and p-FAK. Both compounds also presented low toxicity for healthy cells. Finally, this work provides the first insights into the effects of these cardenolides on key steps of lung cancer metastasis.

/ALTERNATIVE and IN VITRO TESTS/ Autophagy and apoptosis are important processes that control cellular homeostasis and have been highlighted as promising targets for novel cancer therapies. Here, we identified convallatoxin (CNT), isolated from Antiaris toxicaria, as a dual inducer of autophagy and apoptosis. CNT exerts cytotoxic effects on a number of cancer and normal cell lines and induces apoptosis by increasing caspase-3 and poly ADP ribose polymerase (PARP) cleavage. Moreover, dose- and time-dependent autophagic activity was detected in CNT-treated cells, and mammalian target of rapamycin (mTOR)/p70S6K signal pathway inhibition was observed. Notably, CNT inhibits human umbilical vein endothelial cell (HUVEC) growth and exerts anti-angiogenic activity in vitro and in vivo. Collectively, these results demonstrate that the naturally occurring compound, CNT, is a novel anti-angiogenic compound via dual inducing of autophagy and apoptosis.

/ALTERNATIVE and IN VITRO TESTS/ Cardenolides are cardiac glycosides, mostly obtained from natural sources. They are well known for their inhibitory action on the Na,K-ATPase, an effect that regulates cardiovascular alterations such as congestive heart failure and atrial arrhythmias. In recent years, they have also sparked new interest in their anticancer potential. In the present study, the cytotoxic effects of the natural cardenolide convallatoxin (CON) were evaluated on non-small cell lung cancer (A549) cells. It was found that CON induced cytostatic and cytotoxic effects in A549 cells, showing essentially apoptotic cell death, as detected by annexin V-propidium iodide double-staining, as well as changes in cell form. In addition, it prompted cell cycle arrest in G2/M and reduced cyclin B1 expression. This compound also increased the number of cells in subG1 in a concentration- and time-dependent manner. At a long term, the reduction of cumulative population doubling was shown along with an increase of beta-galactosidase positive cells and larger nucleus, indicative of senescence. Subsequently, CON inhibited the Na,K-ATPase in A549 cells at nM concentrations. Interestingly, at the same concentrations, CON was unable to directly inhibit the Na,K-ATPase, either in pig kidney or in red blood cells. Additionally, results of docking calculations showed that CON binds with high efficiency to the Na,K-ATPase. Taken together, our data highlight the potent anticancer effects of CON in A549 cells, and their possible link with non-classical inhibition of Na,K-ATPase.

/LABORATORY ANIMALS: Acute Exposure/ When administered in a single iv injection at minute to lethal doses to rats or cats, convallatoxin caused vascular disorders in the heart, liver, and kidneys. When injected daily at doses corresponding to 0.2 to 0.4 LD100 for 15 days, it caused dystrophic changes and increased the infiltration and proliferation processes.

/LABORATORY ANIMALS: Acute Exposure/ The effects of a single or repeated ip injections of convallatoxin on the histology of the heart, liver, kidney, spleen, and lungs was studied in mice, rats, and cats. A single injection dilated blood vessels in the heart, liver, and kidneys, caused hemorrhage in the liver, and caused an infiltrative-proliferative effect in the heart and liver. After chronic injections, the infiltrative-proliferative effect was more pronounced than after the acute administration, and dystrophic changes were observed in the liver.

/LABORATORY ANIMALS: Acute Exposure/ When injected iv into mice, the LD50 value of convallatoxin was 6.3 mg/kg. The glycoside caused tremor, convulsions, and paralysis of the limbs and affected respiration. The preparation caused disorders in the cardiac activity and a transient coronary insufficiency.

/LABORATORY ANIMALS: Neurotoxicity/ Iv injection of convallatoxin at 0.1 mg/kg induced a hyperbaric slow-wave sleep in the cerebral cortex of rabbits. The brain content of 5-hydroxytryptamine did not change markedly. It increased slightly following iv injection of convallatoxin at 0.15 mg/kg. The possible mechanisms of the CNS-inhibitory and central arrhythmic effects of convallatoxin is discussed.

For more Non-Human Toxicity Excerpts (Complete) data for Convallatoxin (7 total), please visit the HSDB record page.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

LD50 Mice ip 10 mg/kg

LD50 Rat iv 15 mg/kg

LD50 Mice sc 15 mg/kg

LD50 Mice iv 1 mg/kg

For more Non-Human Toxicity Values (Complete) data for Convallatoxin (6 total), please visit the HSDB record page.

Naturally occurring in lily of the valley blossoms; Used as a cardiotonic and veterinary diuretic; [Merck Index]

MEDICATION

Convallatoxin is a glycoside extracted from Convallaria majalis. Convallatoxin is also isolated from the trunk bark of Antiaris toxicaria (A15340).

Convallatoxin batches made in Switzerland, West Germany, and Britain contained periguloside, convallatoxol, aglycons, and noncardenolides. The impurities were removed by column chromatography on neutral aluminum oxide-silica gel (1:1) by elution with CHCl3-ethanol (4:1).

... Convallaria majalis (Lily of the Valley), yields cardiac glycoside, convallatoxin, which is not employed clinically but which possesses potent characteristic digitalis-like activity.

A phytotoxin from the flowers of Adonis vernalis, convallaria majalis, ornthogalum umbellatum and antiaris toxicaria. The aglycone is convallatoxigenin and the sugar is a rhamnose.